Simultaneous siRNA Targeting of Src and Downstream Signaling Molecules Inhibit Tumor Formation and Metastasis of a Human Model Breast Cancer Cell Line

被引:39
作者
Bjorge, Jeffrey D. [1 ,4 ]
Pang, Andy S. [1 ,4 ]
Funnell, Melanie [1 ,4 ]
Chen, Ke Yun [1 ,4 ]
Diaz, Roman [2 ,3 ]
Magliocco, Anthony M. [2 ,3 ]
Fujita, Donald J. [1 ,4 ]
机构
[1] Univ Calgary, So Alberta Canc Res Inst, Calgary, AB, Canada
[2] Univ Calgary, Dept Oncol, Calgary, AB, Canada
[3] Univ Calgary, Dept Pathol & Lab Med, Calgary, AB, Canada
[4] Univ Calgary, Dept Biochem & Mol Biol, Calgary, AB, Canada
关键词
PANCREATIC ADENOCARCINOMA CELLS; TYROSINE KINASE-ACTIVITY; C-SRC; RNA INTERFERENCE; PHOSPHATASE-ACTIVITY; MDA-MB-435; CELLS; GENE-EXPRESSION; MYC EXPRESSION; PROTECTS MICE; GROWTH-FACTOR;
D O I
10.1371/journal.pone.0019309
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Background: Src and signaling molecules downstream of Src, including signal transducer and activator of transcription 3 (Stat3) and cMyc, have been implicated in the development, maintenance and/or progression of several types of human cancers, including breast cancer. Here we report the ability of siRNA-mediated Src knock-down alone, and simultaneous knock-down of Src and Stat3 and/or cMyc to inhibit the neoplastic phenotype of a highly metastatic human model breast cancer cell line, MDA-MB-435S, a widely used model for breast cancer research. Methodology/Results: Src and its downstream signaling partners were specifically targeted and knocked-down using siRNA. Changes in the growth properties of the cultured cancer cells/tumors were documented using assays that included anchorage-dependent and -independent (in soft agar) cell growth, apoptosis, and both primary and metastatic tumor growth in the mouse tumor model. siRNA-mediated Src knock-down alone, and simultaneous knock-down of Src and Stat3 and/or cMyc inhibited the neoplastic phenotype of a highly metastatic human model breast cancer cell line, MDA-MB-435S. This knock-down resulted in reduced growth in monolayer and soft agar cultures, and a reduced ability to form primary tumors in NOD/SCID mice. In addition, direct intra-tumoral injection of siRNAs targeting these signaling molecules resulted in a substantial inhibition of tumor metastases as well as of primary tumor growth. Simultaneous knock-down of Src and Stat3, and/or Myc exhibited the greatest effects resulting in substantial inhibition of primary tumor growth and metastasis. Conclusions/Significance: These findings demonstrate the effectiveness of simultaneous targeting of Src and the downstream signaling partners Stat3 and/or cMyc to inhibit the growth and oncogenic properties of a human cancer cell line. This knowledge may be very useful in the development of future therapeutic approaches involving targeting of specific genes products involved in tumor growth and metastasis.
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页数:11
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